Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstrasse 48, 48149 Münster, Germany.
Med Chem. 2024;20(10):969-985. doi: 10.2174/0115734064320241240709114041.
Cytosolic phospholipase A2α (cPLA) is the key enzyme that initiates the arachidonic acid cascade through which pro-inflammatory lipid mediators can be formed. Therefore, cPLA is considered an interesting target for the development of anti-inflammatory drugs. Although several effective inhibitors of the enzyme have been developed, none of them has yet reached clinical application.
Recently, we have prepared new 4-sulfamoylbenzoic acid derivatives based on a cPLA inhibitor found in a ligand-based virtual screening. The most effective of these compounds were now subjected to further variations in which the substitution pattern on the sulfamoyl nitrogen atom was changed..
The new compounds were tested in a vesicle assay for cPLA inhibition as well as for their water solubility, metabolic stability, and selectivity towards related enzymes. In addition, they were evaluated in a whole blood assay in which metabolites of the arachidonic acid cascade formed after activation of cPLA were quantified using a combined online dilution/ online solid phase extraction HPLC-MS method.
Inhibitors with submicromolar inhibitory potency were found with favourable water solubility and selectivity. However, their efficacy did not match that of the highly effective, known, structurally related cPLA inhibitor giripladib, which was also tested as a reference. One advantage of some of the new compounds compared to giripladib was their significantly improved water solubility. When analyzing the substances in the whole blood assay, it was found that the obtained inhibition data correlated better with the results when the phorbol ester 12-Otetradecanoylphorbol- 13-acetate was used for activation of the enzyme in the blood cells instead of the calcium ionophore A23187.
New compounds with good activity towards cPLA and reasonable physicochemical properties were identified. Overall, the results obtained could be helpful in the development of clinically applicable inhibitors of this enzyme.
细胞质型磷脂酶 A2α（cPLA）是启动花生四烯酸级联反应的关键酶，通过该反应可以形成促炎脂质介质。因此，cPLA 被认为是开发抗炎药物的一个有趣靶点。尽管已经开发出几种有效的该酶抑制剂，但没有一种已经达到临床应用。
最近，我们根据配体基虚拟筛选中发现的 cPLA 抑制剂，制备了新的 4-磺胺甲酰苯甲酸衍生物。这些化合物中最有效的化合物现在进行了进一步的变化，改变了磺胺甲酰氮原子上的取代模式。
在囊泡测定中测试新化合物对 cPLA 的抑制作用，以及它们的水溶性、代谢稳定性和对相关酶的选择性。此外，还在全血测定中对它们进行了评估，在该测定中，使用在线稀释/在线固相萃取 HPLC-MS 方法定量测定 cPLA 激活后形成的花生四烯酸级联代谢物。
发现具有亚微摩尔抑制效力的抑制剂具有良好的水溶性和选择性。然而，它们的功效并不匹配高度有效的、结构相关的已知 cPLA 抑制剂 giripladib，后者也作为参考进行了测试。与 giripladib 相比，一些新化合物的一个优点是它们的水溶性有了显著提高。在全血测定中分析这些物质时，发现获得的抑制数据与用细胞中的佛波醇 12-O-十四烷酰佛波醇-13-乙酸酯代替钙离子载体 A23187 激活酶时得到的结果相关性更好。
鉴定出对 cPLA 具有良好活性且具有合理物理化学性质的新化合物。总的来说，这些结果可能有助于开发该酶的临床应用抑制剂。
